Method for making freeze dried drug dosage forms

ABSTRACT

The present invention discloses an improved technique for preparing a rapidly dispersing pharmaceutic tablet of a granular therapeutic agent which has both relatively low solubility and relatively large particle size. Xanthan gum is added to a liquid admixture of solvent, carrier components, and the granular therapeutic agent. The xanthan gum not only facilitates suspension of the granular therapeutic agent in the liquid admixture, but, more surprisingly, does so without adversely effecting the dispersion qualities and texture of the tablet in the patient&#39;s mouth upon administration.

This application is a 371 of PCT U.S. Ser. No. 94/07618.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

This invention concerns an improved method for manufacturing atherapeutic tablet that dissolves nearly instantaneously upon contactwith water. This method improves upon traditional freeze-dry methodswhich include preparing an aqueous suspension containing a granulartherapeutic agent, placing the aqueous suspension in molds, and freezedrying the aqueous suspension to produce a solid pharmaceutic tablet.The improved method of this invention incorporates a particular agentinto the aqueous gelatin containing suspension in order to keep thegranular therapeutic agent uniformly dispersed, but does so withoutdegrading the speed of dissolution or the texture and "feel" of thetablet upon dissolution in the mouth.

(2) Description of the Art

Many pharmaceutical dosage forms are administered orally in the form ofsolid, shaped articles such as tablets, pills, and capsules that retaintheir shape under moderate pressure. Generally these dosage forms aredesigned to be swallowed whole, chewed, or retained sublingually orbucally in order to deliver the medication. Some patients, particularlypediatric and geriatric patients, have difficulty swallowing or chewingsolid dosage forms. To assist these patients, therapeutic compounds aresometimes provided as a liquid or suspension. However, these dosageforms are often difficult to distribute and store due to problems withstability. Other patients may not have water available at the time thatthey should take medication, and patient compliance is accordinglyreduced. Still other patients resist taking medication, and may try tohide a solid pill in order to spit it out later.

The prior art discloses methods for manufacturing therapeutic tabletsthat immediately dissolve on contact with saliva in the mouth. Many ofthese prior art manufacturing methods involve freeze drying aqueous drugformulations. U.S. Pat. No. 4,371,516, discloses shaped articles,carrying pharmaceuticals, which disintegrate rapidly in the mouth. Theshaped articles comprise an open matrix of carrier material,interspersed with the medicament. The articles may be prepared bysubliming solvent from a composition comprising the medicament and thecarrier material in solution, the solution being in a solid state in themold.

This unique dosage form provides a solid tablet means for deliveringmedicaments which disintegrates on the tongue of a patient within 10seconds or less. This rapid tablet disintegration rate makes the dosageform suitable for patients who have difficulty swallowing or refuse toswallow conventional tablets containing such medicaments. Further, thedosage form is exceptionally convenient since it does not require theaid of water in order to be swallowed. As such, the rapidlydisintegrating nature of the dosage form and the convenience associatedwith its use offer dramatic improvement in patient compliance andtreatment of disease states.

U.S. Pat. No. 4,305,502, discloses packages containing shaped articlescarrying chemicals, particularly dosage forms carrying pharmaceuticals.The shaped articles, which disintegrate rapidly in saliva, are containedin depressions in sheets of filmic material and are enclosed by acovering sheet adhering to the filmic material. The shaped articles maybe formed in the depressions by a sublimation process.

U.S. Pat. No. 4,758,598, discloses the preparation of solid shapedarticles, particularly pharmaceutical dosage forms, by freezing acomposition comprising a predetermined amount of chemical (e.g., apharmaceutically active compound) and a carrier material solution in amold, and then subliming solvent from the frozen composition. The sidewall or walls of the mold are angled to minimize sublimation times.

U.S. Pat. No. 4,754,597 discloses the preparation of solid shapedarticles, particularly rapidly dissolving pharmaceutical dosage forms.The articles carry predetermined unit quantities of chemicals and aremade by a novel process involving the addition of the predeterminedamount of chemical to a solid sublimed carrier article, prepared byfreeze drying a carrier solution.

U.S. Pat. No. 5,188,825 discloses a freeze-dried dosage form that isprepared from a solution including a bulk forming agent and atherapeutic agent containing ion exchange resin having a particle sizeless than 90 microns. The bulk forming agent may be gelatin or xanthangum. The bulk forming agent is added to the solution to maintain thedispersion of the active agent/ion exchange resin combination.

U.S. Pat. No. 5,206,025 discloses a porous pharmaceutical form and itsmethod of preparation. The porous pharmaceutical form is prepared byfreeze drying a solution including an active substance, binders,diluents, and additives. The binder includes xanthan gum, and gelatin inamounts to yield colloidal solutions.

U.S. Pat. No. 5,272,137 discloses an aqueous pharmaceutical suspensionincluding microcrystalline cellulose and xanthan gum. The solutionformed is capable of forming a suspension of particles ranging in sizefrom 1 to about 850 microns.

Although these prior art freeze dried dosage forms offer many advantagesover hard pills and capsules, the prior art dosage forms are limited incertain respects. For example, the prior art freeze dried dosage formwere limited when used with medicaments that had both relatively lowsolubility in water and relatively large particle size. In suchsituations, the medicament tended to separate out of suspension tooquickly during the manufacturing process, thereby forming an undesirablelayer of sediment at the bottom of the tablet. Although the suspensioncould be extended by use of various thickening agents, these agentstended to degrade the dissolution characteristics of the tablet in themouth.

SUMMARY OF THE INVENTION

This invention is directed to an improved technique for manufacturing afast dissolving therapeutic tablet. It is an object of this invention toprovide a method for preparing a fast dissolving therapeutic agent byfreeze drying a liquid suspension containing a uniformly suspendedgranular therapeutic agent.

This invention is an improvement over prior art processes which providethe basic teaching for preparing freeze dried pharmaceuticals. As notedabove, the basic teachings of this technology are set forth in U.S. Pat.Nos. 4,371,516; 4,305,502; 4,758,598; and 4,754,597, the teachings ofall of which are incorporated herein by reference. The manufacturingmethod uses a pre-prepared liquid composition including a solvent, agranular therapeutic agent, and a gelatin containing carrier material.The liquid composition is placed into one or more shaped depressions ina tray or mold to define liquid composition filled depressions. Theliquid composition in the filled depressions is frozen, then the liquidportion of the liquid composition sublimed to define a solid medicamenttablet. The solid medicament filled trays are then collected.

In the present invention, xanthan gum is added to the liquidcomposition, which is then stirred, prior to the freezing step. Xanthangum behaves synergistically with gelatin as a flocculating agent toimprove the ability of the liquid composition to suspend relativelylarge particles during the manufacturing process. More particularly, itis found that xanthan gum has the ability to improve the suspensionqualities of the liquid composition without degrading the dissolutionqualities and texture of the tablet in the mouth.

In a preferred embodiment, the invention comprises a method of producinga pharmaceutical tablet of famotidine, i.e., a medicament whichfunctions as an H₂ -antagonist. Treatment of the acid-related disordersof the upper gastrointestinal tract, such as reflux disease, oftenrequire life-long therapy with anti-secretary drugs, antacids, or H₂-antagonists such as famotidine. Conventional formulations of thesemedications are large, often difficult to swallow and may require water.These formulations are frequently inconvenient to use. This limitationmay result in poor patient compliance and therefore ineffective therapy.Intravenous (IV) injection of medication is also commonly used, but thishas the obvious disadvantages associated with direct transfer of asolution into the blood stream. In addition, professional medical careis generally required when drugs are introduced in this manner.

The delivery of famotidine or other H₂ -antagonists using a rapidlydisintegrating dosage form would be of tremendous advantage to thepatients in need of such therapy. However, famotidine could not readilybe formulated into the rapidly dispersing dosage form of the prior artbecause of the relatively low solubility and relatively large particlesize of the medicament particles. These obstacles are overcome by theinvention claimed herein.

DESCRIPTION OF THE CURRENT EMBODIMENT

The present invention relates to an improvement in a method ofmanufacturing a fast dispersing therapeutic tablet formulation. Thistherapeutic tablet is formed from a liquid admixture, or suspension,including an inert gelatin containing carrier material, a solvent, and arelatively insoluble therapeutic agent. The invention is particularlyuseful in relation to medicaments having a relatively low solubility anda relatively large insoluble particle size and density. The liquidadmixture is filled into depressions in a tray, which are thereafterfrozen solid. The solid admixture is then subjected to sublimation toproduce a solid medicament tablet. The present method of manufacturing asolid medicament of this invention is an improvement over prior artprocesses in that a suspending agent is added to the liquid admixture inorder to keep the relatively large and insoluble particles of granulartherapeutic agent in suspension prior to freezing and sublimation.

Suspending agents, per se, are not new to pharmaceutical dosage forms ingeneral. In the particular context of freeze dried medicaments, however,is has been found that suspending agents generally degrade thedissolution qualities of the tablet. For example, the suspending agentmay result in a tablet which has a "gummy" texture in the mouth upondissolution. The present invention overcomes that problem.

The method of this invention takes advantage of a synergism betweenxanthan gum and gelatin in which a small concentration of xanthan gum inthe liquid admixture acts as a flocculating agent and cross-links thegelatin. The xanthan gum is a weak cross-linking agent that produces atransient cross linked gelatin containing solution that is stable whenstill and breaks up when disturbed. The gelatin, on the other hand,binds to and coats the granular therapeutic agent. The synergism betweenthe xanthan gum and the gelatin creates a pourable suspension includinga uniformly dispersed granular therapeutic agent. When the concentrationof the xanthan gum falls below a minimum level, the xanthan guminsufficiently cross-links with the gelatin, and a portion of thegranular therapeutic agent can fall out of suspension. When the xanthangum concentration exceeds a certain maximum level then viscositystabilization--keeping solids in solution by causing the solution tobecome viscous--predominates to keep the particles suspended with acommensurate degradation of the dissolution properties of the resultingfreeze dried dosage form.

The general requirements for preparing a freeze dried tablet are wellknown in the art. The liquid admixture used to prepare the easilydissolvable medicament tablets of this invention comprises a solvent, agelatin containing carrier material, a granular therapeutic agent, and asuspending agent. The carrier must be soluble in the chosen solvent.Additionally, the solvent must be inert to the therapeutic agent.However, the granular therapeutic agent need not be soluble in thesolvent, although it may be soluble in the solvent to a limited degree.

Although the medicaments useful with this invention might be describedas having relatively low solubility, the invention is by no meanslimited to medicaments which are considered to be technically"insoluble". Rather, the invention is most useful in connection withmedicaments which, considering both mixing conditions and medicamentconcentration levels, remain at least partially in solid form, i.e., asa suspension of medicament in liquid, when the liquid admixture isfilled into the tray depressions.

Water is preferably employed as the solvent in the liquid admixture,which is frozen and sublimed. An additional co-solvent, such as alcohol,may be used if it is desired to improve the solubility or the wetabilityof any of the ingredients in the composition. It is most preferred thatthe water is deionized water.

By "carrier material" is meant the dosage form excipients which providethe solid matrix support for the granular therapeutic agent after thesolvent is sublimed. The medicament is incorporated within the matrix ofthe carrier material. The carrier material of this invention mustinclude gelatin. Examples of suitable gelatin includes plain gelatin andgelatin that is partially hydrolyzed, for example by heating gelatin inwater. For example, polysaccharide, plain gelatin, and hydrolyzedgelatin have each been tested in the system, and the improvements ofadding xanthan gum have resulted in each. The preferred carrier materialis hydrolyzed gelatin. Examples of other suitable carrier materials thatcan be combined with gelatin are those that are inert andpharmaceutically acceptable for use in preparing pharmaceutical dosageforms. Such carrier materials include polysaccharides such as dextranand polypeptides such as

The liquid admixture also includes a granular therapeutic agent. Thegranular therapeutic agent may be any drug or therapeutic agent that hasa therapeutic effect when administered to humans or animals. The term"granular therapeutic agent" includes agents having an average particlesize ranging from as low as about 1 micrometers to about 400micrometers. Any particulate therapeutic agent which remains at leastpartially in the solid state in the matrix of the carrier material maybe used in the invention. For example, granular therapeutic agents thatmay be used in the liquid composition of this invention include variousbenzodiazepine compounds, acetaminophen and famotidine. In particular,this invention is useful in connection with formulations of famotidine,an H₂ - antagonist having a particle size ranging from less than 1micron to about 400 microns and more.

The granular therapeutic agents used in the liquid admixture have atendency to settle to the bottom of both the vessels in which the liquidadmixture is prepared and the depressions filled with the liquidcomposition. This settling effect results in a nonuniform medicamenttablet. Therefore, the liquid admixture useful in this inventionincludes a suspending agent. The suspending agent cross-links thegelatin coated granular therapeutic agent and keeps the granulartherapeutic agent dispersed in the liquid admixture until the time thatthe liquid admixture is frozen. Alternatively, when the chosen granulartherapeutic agent is soluble in the solvents to a limited degree, thesuspending agents aid in the solubilization of the therapeutic agent toproduce a uniform liquid composition. "Suspending agents" includes anyagent that facilitates preventing the settling of the granulartherapeutic agent in the liquid admixture of this invention. A preferredsuspending agent is xanthan gum, and is commercially available from, forexample, Rhone-Poulenc, Cranbury, N.J. In preferred embodiments, xanthangum comprises from about 0.001 to 1% by weight of the liquid admixture,and in particularly preferred embodiments, xanthan gum comprises fromabout 0.01 to about 0.05% by weight of the admixture. Above 0.05% byweight in a gelatin/famotidine carrier matrix, the xanthan gum actspredominantly as a viscosity modifier thereby retarding the dissolutionproperties of the resulting freeze dried dosage form.

The pH of the liquid admixture is also important and should bemaintained at from a pH of from 4 to 8 to maintain the flocculatingeffect of the suspending agent. Preferably the pH of the liquidadmixture is from 6 to 8 when the suspending agent is xanthan gum.Within this range, the charged therapeutic agent particles aresurrounded by positively charged gelatin which in turn is cross-linkedwith a charged suspending agent such as xanthan gum. A suspending agentsuch as xanthan gum loses its flocculating effect outside of this narrowpH range.

As previously noted, this invention has particular advantages when usedin conjunction with medicaments having a relatively large particle sizeand weight. That is, the invention is particularly useful in relation tomedicaments whose particle size and weight cause them to settle out ofsuspension relatively quickly. The size and weight relationship may be,but is not necessarily, related to physical characteristics of themedicament in the dry condition. For example, as previously noted,medicaments may have a relatively large particle size and weight in thedry state, but may also have a low degree of solubility causing them topartially dissolve during preparation of the liquid admixture. Yet,depending on starting size and relative solubility, the particles mayremain in solid particulate suspension to a significant degree andmaintain a relatively large particle size and weight in suspension.Within this understanding, the present invention is directed tomedicaments having a particular size and weight ratio in suspension. Theaverage particle size of the medicament particle is generally greaterthan about 50 micrometers. In preferred form, the size of the medicamentparticles is between about 5 micrometers and about 400 micrometers.

Varying amounts of the H₂ -antagonists or other antagonist may beincluded within the dosage form. For example, the dosage form maycontain from about 1 mg to about 500 mg of famotidine. In preferredforms, the dosage form would contain either approximately 10, 20, 40 or120 mg. of famotidine. The famotidine used in connection with theexamples described herein had an average dry-state particle size ofbetween about 20 micrometers and about 100 micrometers.

The liquid admixture useful in the method of this invention may containother additional, optional ingredients. For example, the liquidadmixture may include pharmaceutically acceptable adjuvants such ascoloring agents, flavoring agents, preservatives, surfactants, and anyother materials that can be incorporated into pharmaceuticalpreparations.

Among the coloring agents which may be employed are dyestuffs, pigments,and non-dispensable coloring agents. In the preferred embodiment,Opatint AD 25000, a micronized dispersion of red ferric oxide, availablefrom Colorcon, Inc., West Point, Pa. The amount of coloring agent usedin each dosage form may vary from about 0.08 mg to about 3.00 mg/dosageform.

Among the flavoring enhancers which may be employed are the following:banana, wild cherry, peppermint, strawberry, aniseed, black currant,grapefruit, caramel, raspberry, lemon, tutti frutti, cinnamon, lime,orange, spearmint, eugenol or any combination of these flavoringingredients. In the preferred embodiment, aspartame, obtained from ForumChemicals, Ltd., Forum House, 41 Brighton Road, Redhill, Surrey, U.K.,and peppermint oil or powder, obtained from Firmenich U.K., Ltd., HaysRoad, Southhall, Middlesex, U.K., were combined in a ration of about15:1 to introduce an acceptable flavor to the final solid dosage form.The total amount of flavor enhancer may range from about 0.10 mg toabout 2.50 mg/dosage form.

The liquid admixture of this invention is typically prepared in a largebatch and the batch is divided into small controlled doses by fillingthe liquid admixture into one or more shaped depressions in a moldedtray. Generally, the shape of the depression will correspond to the sizeand shape of the desired dosage form. A plurality of shaped depressionswill generally be formed in a sheet of filmic material. For example, thefilmic material may be made of a thermoplastic material with thedepressions formed by thermal forming.

The type of filmic material used is not critical to the instantinvention. However, the filmic material should resist the transmissionof to moisture and the filmic material should be compatible with a coveror with some other means for sealing the depression containing filmicmaterial from the environment. The filmic material is generally the sameor similar to the material use in conventional blister packs. Among thefilmic materials that may be utilized are the following: polyvinylchloride, laminates of filmic material such as polyvinylchloride/polyvinylidene chloride, polyvinylchloride/polytetra-fluoroethylene or polyvinylchloride/polyethylene/polyvinylidine chloride. The filmic material mayalso be prepared from polypropylene which may be used alone or inconjunction with polyethylene terephthalate glycol and othernon-chlorinated materials. Other materials which have suitableintegrity, are inert towards the formulation and have the thermalstability required to withstand the freeze cycle and sublimation processare also included within the scope of this invention.

The liquid admixture may be filled into the depressions by any meansknown to the art. Similarly, the liquid filled depressions may be frozenby any method known in the art capable of producing a sublimable frozenarticle. Preferably, the liquid admixture is frozen in a liquid nitrogenor a liquid carbon dioxide freezer. The freezer should operated at atemperature that is low enough to completely solidify the admixture.

The frozen solvent portion of the admixture is preferably thereaftersublimed. Sublimation is preferably achieved in a freeze-drier bysubjecting the now-solid admixture in the depression to a reducedpressure, followed by controlled application of heat to aid thesublimation. At this point the freeze drier temperature may be adjustedupward to speed up sublimation. When the sublimation is complete, thefreeze drier is pressurized to atmospheric pressure and the now solidmedicament tablets are removed from the freeze drier and recovered. Thesolid medicament tablets may be recovered by removing them from thedepressions or by sealing the solid medicament tablets into thedepression with, for example, a sheet of plastic film that is thermallyor adhesively attached to the depression filled tray.

EXAMPLES

A fast dissolving, solid, oral, medicament tablet, delivering about 10,20 or 40 mg of famotidine per dosage form, was prepared using thefollowing procedures.

Example 1

Preparation of Premix

The ingredients of Table 1 were added to a mixing bowl and dry mixed forfive (5) minutes:

                  TABLE 1                                                         ______________________________________                                        CARRIER MATERIAL                                                                       Amount Used for Stated Potency                                       Ingredient 10 mg       20 mg     40 mg                                        ______________________________________                                        Gelatin    577.98   g      540.00                                                                              g   540.00 g                                 Mannitol   765.00   g      490.90                                                                              g   490.86 g                                 Xanthan Gum                                                                              5.94            5.40  g   5.40   g                                 ______________________________________                                    

Water was added to the mixing bowl and the ingredients were mixed untila uniform paste was obtained. The amount of water used to prepare thesuspension is shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        WATER REQUIREMENT                                                                      Amount H.sub.2 O Used for Stated Potency                             Stated Potency                                                                            10 mg      20 mg     40 mg                                        ______________________________________                                        Paste       1.60    kg     1.60  kg  1.60   kg                                Production                                                                    Dilution Step                                                                             13.818  kg     13.510                                                                              kg  13.377 kg                                ______________________________________                                    

A partial vacuum of about 0.8 to about 0.9 bar was applied to the mixingbowl and the amount of deionized water for the dilution step, shown inTable 2, was added. The mixture was stirred under vacuum for anadditional 15 minutes.

The mixture was then heated to 40±2° C. and homogenized for 10 minuteswhile maintaining the partial vacuum of about 0.8 to about 0.9 bar. Thehomogenized mixture was cooled to about 23±1° C. and filtered through a38 micron filter.

In a separate mixing bowl, the amount of Optaint AD 25000 shown in Table3, and the amount of deionized water shown in Table 3, were mixed andsonicated until the Opatint suspension was fully dispersed. Thissuspension was then added to the mixture containing gelatin, mannitoland xanthan gum prepared previously.

                  TABLE 3                                                         ______________________________________                                        COLORING AGENT PREPARATION                                                    Potency        Opatint AD 25000                                                                           Water                                             ______________________________________                                        10 mg/lozenge  54.00    g       240    g                                      20 mg/lozenge  7.20     g       200    g                                      40 mg/lozenge  90.00    g       250    g                                      ______________________________________                                    

The mixture containing the Optaint was then homogenized under a partialvacuum of about 0.8 to about 0.9 for about 5 minutes.

Example 2

Preparation of Famotidine Suspension

In processing the 10 mg dosage form, about 3 kg of the premix weretransferred to a mixing vessel containing a homogenizer. Whilehomogenizing the premix, 782.64 g of famotidine were gradually added tothis portion of the premix. Once the famotidine was completelydispersed, the suspension was transferred to a mixer and mixed under apartial vacuum of about 0.8 to about 0.9 bar to assure adequatedeaeration of the suspension. The formulation was brought to ambientpressure and an amount of aspartame and peppermint flavor as shown inTable 3, were added to the suspension of the remainder of the premix wasadded with stirring. The final mixture was homogenized under a partialvacuum of about 0.8 to about 0.9 bar for 10 minutes. The resultingsuspension was transferred to a storage vessel.

In processing the 20 and 40 mg dosage forms, the procedure was modifiedto assure uniform mixing of the increased amount of famotidine in thefinal formulation. For these potencies, about 3 kg of the premix weretransferred to a mixing vessel containing a homogenizer. Whilehomogenizing the premix, about 700 g of famotidine were gradually addedto this portion of the premix. This step was repeated using a further 3kg quantity of premix and an additional 740 g of famotidine. Once thedrug was fully dispersed, the total suspension was transferred to avessel and homogenized together for 10 minutes. The suspension was thentransferred to a mixer under a partial vacuum of about 0.8 to 0.9 bar toassure adequate deaeration of the suspension. The formulation wasbrought to ambient pressure and the amount of aspartame and peppermintflavor shown in Table 3 were added to the suspension and the remainderof the premix was added with stirring. The final mixture was homogenizedunder a partial vacuum of about 0.8 to about 0.9 bar for 10 minutes. Theresulting suspension was transferred to a storage vessel.

                  TABLE 4                                                         ______________________________________                                        ASPARTAME AND                                                                 PEPPERMINT FLAVOR REQUIREMENTS                                                Potency       Aspartame Peppermint Flavor                                     ______________________________________                                        10 mg/lozenge 146.70  g     9.72    g*                                        20 mg/lozenge 135.00  g     72.00   g**                                       40 mg/lozenge 135.00  g     72.00   g**                                       ______________________________________                                         *The peppermint flavor used for the 10 mg lozenge was provided as an oil.     **The peppermint flavor used for the 20 and 40 mg lozenges was provided a     a powder.                                                                

Example 3

Filling and Freeze Drying of the Suspension

An amount of suspension (shown in Table 4) was dispensed into eachdepression in a polyvinyl chloride tray. The depressions werecylindrical in nature having volumes and diameters shown below. Therewere 100 to 180 depressions in each tray. The tray was then movedthrough a freeze tunnel which was maintained at a temperature of fromabout -20° C. to about -160° C. to assure that the dosage forms werecompletely frozen.

                  TABLE 4                                                         ______________________________________                                        WEIGHT OF SUSPENSION DISPENSED PER LOZENGE.                                              Weight    Depression                                               Potency    Dispensed Volume    Depression Dia.                                ______________________________________                                        10 mg/lozenge                                                                            0.23   g      230  mL   12     mm                                  20 mg/lozenge                                                                            0.25   g      250  mL   12     mm                                  40 mg/lozenge                                                                            0.50   g      500  mL   16     mm                                  ______________________________________                                    

As the trays emerged from the freeze tunnel, they were either stored atabout -20° C. or placed immediately into the freeze drier.

The shelf of the freeze drier is maintained at a temperature of fromabout -20° C. to about -10° C. Once the sublimation process wasinitiated, a partial vacuum of about 0.25 to about 1.00 m bar wasapplied within the freeze drier.

Example 4

Disintegration Testing

Samples of the dosage forms prepared using the procedures stated in theExamples above were tested for disintegration time as follows: Fivebreakers filled with distilled water are placed in a water bathcontrolled at 37° C. Five dosage forms are each secured in a wire clipweighing 0.5 g plus or minus 0.05g. The weighted dosage forms are eachplaced in a discrete tube in a gauze covered basket. The baskets arethen lowered at a constant rate into the breakers, one basked to abreaker. The disintegration time is measured from starting the raisingand lowering mechanism to the time the last dosage form disintegrates.Disintegration is complete when the wetted mass has passed through thegauze, or the gauze is visible through the remaining mass. As the datain Table 1 indicate, each of the dosage forms tested disintegratedwithin 10 seconds.

    ______________________________________                                        FAMOTIDILNE ZYDIS DISINTEGRATION TIMES                                                 Disintegration Time (Seconds)                                        ______________________________________                                        20 mg 12 mm Formula                                                           Batch 1    1.09                                                               Batch 2    1.85                                                               Batch 3    1.68                                                               *Mean      1.54                                                               40 mg 16 mm Formula                                                           Batch 1    1.09                                                               Batch 2    1.18                                                               Batch 3    1.30                                                               *Mean      1.19                                                               ______________________________________                                         *The two decimal figures should not be taken as indicative of the accurac     of the timing. This is simply the value recorded by the stopwatch which i     controlled by hand.                                                      

Example 5

Rate of Solution Samples of the dosage form prepared using the procedureoutlined above were tested for rate of solution using the USP Apparatus2 (paddles) (U.S. Pharmacopeia, XXII p.1578.) The testing was conductedusing 900 ml of distilled, deionized water which was maintained at37°±0.5° C. throughout the testing period. Famotidine was determined byreverse phase HPLC using a Hypersil column with a mobile phase of 7% CH₃CN in CH₃ COONa (pH 8.0) with a UV detection at 270 nm. Results fromeach of four formulations of famotidine are presented in Table 5. Theseresults demonstrate both the uniformity of the H₂ -antagonist and alsothe rapid delivery capability of the dosage form.

                  TABLE 5                                                         ______________________________________                                        RATE OF SOLUTION OF FAMOTIDINE FREEZE DRIED                                   LOZENGE                                                                       Average % of Claim Famotidine dissolved at Stated Time                        Potency      2 min.      5 min.  8 min.                                       ______________________________________                                        10 mg/lozenge                                                                              79%         87%     101%                                         20 mg/lozenge                                                                              83%         95%     100%                                         40 mg/lozenge                                                                              83%         95%      99%                                         ______________________________________                                    

Example 6

Uniformity of the Dosage Form

In order to demonstrate the uniformity of the resulting dosage form, tenlozenges from each of four different potencies of freeze dried lozengescontaining famotidine were tested by dissolving the dosage forms in0.01M pH 7 phosphate buffer and quantifying the dissolved famotidineusing HPLC with a Hypersel C₁₈, 15 cm column maintained at 40° C. with amobile phase of acetonitrile and 0.1M sodium acetate buffer at pH 6.0.UV detection was utilized at a wavelength of 275 nm. The results of thisstudy are shown in Table 6.

                  TABLE 6                                                         ______________________________________                                        DOSAGE FORM UNIFORMITY                                                        mg/Lozenge                                                                    Potency        Range    Average                                               ______________________________________                                        10              9.7-10.4                                                                              10.1                                                  20             20.0-21.0                                                                              20.5                                                  40.            40.7-41.8                                                                              41.1                                                  ______________________________________                                    

These results clearly show that xanthan gum produces solid medicamenttablets of uniform dosage.

The foregoing specification provides a description of certain aspects ofthe invention in relation to particular preferred embodiments. It iscontemplated, however, that the invention may find use and be adoptedfor use in applications and embodiments other than those describedherein. Accordingly, the invention is to be limited only by thefollowing claims and their equivalents.

What is claimed is:
 1. A method of manufacturing a solid, shaped dosageform which disintegrates in lass than about 10 seconds upon contact withan aqueous media, said method including the preparation of a liquidadmixture comprising a solvent, gelatin, a granular therapeutic agenthaving a particle size ranging from about 1 to about 400 microns andfrom 0.01 to 0.05 weight percent xanthan gum sufficient to actpredominantly as a gelatin flocculating agent; filing said liquidadmixture into one or more shaped depressions in a tray; freezing saidliquid admixture in said trays so as to form solid shaped admixtures ofsolvent, carrier and granular therapeutic agent; and removal of saidsolvent so as to form a solid shaped tablet of carrier matrix andgranular therapeutic agent.
 2. The method of claim 1 wherein xanthan gumis added to the liquid admixture prior to the addition of the granulartherapeutic agent to said liquid admixture.
 3. The method of claim 1wherein the solvent used to prepare the liquid admixture comprises anaqueous solvent.
 4. The method of claim 1 wherein the solvent used toprepare the liquid admixture is removed by freeze drying.
 5. The methodof claim 1 wherein the granular therapeutic agent is famotidine.
 6. Themethod of claim 1 wherein the pH of the admixture is from 6.0 to 8.0. 7.A method for manufacturing a solid, shaped pharmaceutical dosage formwhich disintegrates in less than about 10 seconds upon contact with anaqueous media by the steps comprising preparing a liquid admixtureincluding a solvent, gelatin, famotidine having a particle size range offrom about 0 to about 400 microns, and xanthan gum in an amount fromabout 0.01 to 0.05 weight percent of the carrier matrix; filling saidliquid admixture into one or more shaped depressions in a tray; freezingsaid liquid admixture in said tray so as to form a solid shapedadmixture of solvent, carrier and granular therapeutic agent; andremoval of said solvent so as to form a shaped tablet of carrier matrixand granular therapeutic agent.
 8. The improved pharmaceutical dosageform of claim 7 wherein xanthan gum is added to the liquid admixtureprior to the addition of the granular therapeutic agent to said liquidadmixture.
 9. The improved pharmaceutical dosage form of claim 7 whereinthe pH of the admixture is from about 6 to about
 8. 10. A solid, shapedfamotidine dosage form made by preparing a liquid admixture having a pHof from 6 to 8 comprising a solvent, gelatin, famotidine having aparticle size of from i to 400 microns, and xanthan gum in an amountranging from about 0.01 and 0.05 percent by weight of the carriermatrix; filling said liquid admixture into one or more shapeddepressions in a tray; freezing said liquid admixture in said tray so asto form a solid shaped admixture of solvent, carrier and famotidine; andremoval of said solvent so as to form a shaped tablet of carrier matrixand famotidine.